Friedreich ataxia (FRDA), an autosomal progressive recessive neurodegenerative disorder associated with cardiomyopathy, is caused by reduced expression of the mitochondrial protein, frataxin [V. Campuzano et al., 1996 and V. Campuzano et al., 1997]. The cardiomopathy associated with FRDA is hypertrophic. As the disease progresses, there is a natural transition from hypertrophy to dilation, with death of cardiomyocytes replaced by fibrotic tissue leading to systolic and diastolic dysfunction [R. M. Payne et al., 2012]. Impaired myocardial perfusion reserve index associated with microvascular dysfunction and fibrosis occurs even prior to the onset of overt cardiomyopathy. Consistent with impaired mitochondrial respiratory chain function that leads to energy deficit, phosphorus magnetic resonance spectroscopy shows reduced ATP production in patient heart, which strongly correlates with the degree of cardiac hypertrophy. Cardiac dysfunction, predisposing to congestive heart failure and supraventricular arrhythmias, is the primary mode of death in ˜60% of patients with FRDA.
Although the function of frataxin is still under investigation, available evidence supports a role as an activator of iron-sulfur (Fe—S) cluster biogenesis in mitochondria [C. L. Tsai et al., 2010 and Schmucker et al., 2012]. In particular, frataxin was recently shown to control iron delivery for de novo Fe—S cluster biogenesis through activation of cysteine desulfurase activity [Colin et al., 2013].
Fe—S clusters are essential prosthetic groups for many proteins with a variety of functions and subcellular localizations. Frataxin deficiency leads to impairment of Fe—S cluster-containing proteins, altered cellular iron metabolism, mitochondrial dysfunction and increased sensitivity to oxidative stress. Most mitochondrial and biochemical defects identified in human patients have been recapitulated in mouse models of FRDA [H. Puccio et al., 2001 and Simon et al. et al., 2004], providing valuable models for testing potential therapeutic interventions. Particularly, the MCK conditional mouse model, with complete frataxin deletion in cardiac and skeletal muscle, recapitulates the cardiomyopathy observed in FRDA patients with a more rapidly progressive course [H. Puccio et al., 2001 and H. Seznec et al., 2004]. Furthermore, the MCK mouse demonstrated that hypertrophy and mitochondrial Fe—S cluster protein defects precede mitochondrial iron accumulation and increase sensitivity to oxidative stress.
To date, no treatment exists for stopping or slowing down the cardiomyopathy of FRDA. Current therapeutic approaches in clinical use or under evaluation are directed at alleviating symptoms and maximizing quality of life [R. B. Wilson 2012]. Thus, there is an important need for a novel therapeutic approach to treat cardiomyopathy associated with Friedreich ataxia.